tbuckley/cabot-search huggingface dataset:
Colorectal cohort analysis from the Intraperitoneal Chemotherapy After Cytoreductive Surgery for Peritoneal Metastasis (ICARuS) clinical trial.
Authors: Garrett Michael Nash, Julio Garcia-Aguilar, Philip Paty, Mithat Gonen, Michael Bonner Foote, Sebastian Chung, Mostafa Mohamed, Nicole Aguirre, Martin R. Weiser, Rachel Rassam, Jose G. Guillem, Jesse Joshua Smith, Emmanouil Pappou, Iris H Wei, Parisa Momtaz, Marc J Gollub, Efsevia Vakiani, Jinru Shia, Leonard B. Saltz, Andrea Cercek
Journal: Journal of Clinical Oncology (2023)

160 Background: ICARuS is a randomized phase II, multicenter trial to evaluate the relative efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C vs. Early Postoperative Intraperitoneal Chemotherapy (EPIC) with floxuridine (FUDR), after cytoreductive surgery (CRS), for the treatment of peritoneal metastases (PM) from colorectal (CRC) or appendiceal cancer (AC). PRODIGE7 results failed to demonstrate benefit of HIPEC therapy after complete gross resection of CRC PM, prompting termination of CRC accrual and early cohort analysis. Methods: Patients with isolated, confirmed PM were eligible for 1:1 randomization to CRS plus HIPEC with mitomycin C or CRS plus EPIC with FUDR. Patients were stratified by recent systemic chemotherapy and disease (AC vs. CRC). The trial was originally powered to evaluate 212 patients for a 20% gain in a primary endpoint of 3-year progression free survival (PFS: HR = 1.75). Results: Seventy-five CRC patients were included between 4/2013 and 12/2018 for HIPEC (N = 40) or EPIC (N = 35) treatment. Baseline characteristics were well balanced. After a median follow up of 36 months, the median PFS was 7.7 months (95% CI: 6.3-11.1) in the HIPEC arm and 8.8 months (95% CI: 7.1-21.9) in the EPIC arm, HR = 0.69 (95% CI: 0.42-1.14) p = 0.14. In the 42 left-sided primary cancers, the median PFS was 8.4 months (95% CI: 6.4-17.7) in the HIPEC arm and 12.5 months (95% CI: 8.1-NR) in the EPIC arm, HR = 0.60 (95% CI: 0.29-1.22) p = 0.14. In the 33 right-sided primary cancers, the median PFS was 6.5 months (95% CI: 5.5-14.1) in the HIPEC arm and 8 months (95% CI: 5.8-24.1) in the EPIC arm, HR = 0.80 (95% CI: 0.39-1.64) p = 0.53. PFS was significantly better in the EPIC arm among patients with BRAF wildtype (WT) tumors and patients with higher PM burden (PCI &gt; 7). There was no difference between HIPEC and EPIC in the primary toxicity endpoint of complications grade 3 or above (23 vs. 34%, p = 0.3). Conclusions: Three-year PFS did not significantly differ between treatment arms. The lack of survival benefit of HIPEC in the entire cohort and in subset analysis is consistent with the findings of PRODIGE7. ICARuS remains open to accrual for AC. These data support further investigation of the potential benefit of EPIC with CRS in carefully selected patients with CRC PM. Clinical trial information: NCT01815359 .
Greco-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.
Authors: Todd Anthony Aguilera, Parag Parikh, Maged Ghaly, Sarah E. Hoffe, Joseph M. Herman, Joseph Michael Caster, Dae Won Kim, James Costello, Mokenge Peter Malafa, Muhammad S. Beg, Elizabeth Charlotte Moser, Eugene Paul Kennedy, Kara Terry, Michael Kurman
Journal: Journal of Clinical Oncology (2023)

TPS766 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks. Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide. Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety. In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial (NCT04698915) is now enrolling. Clinical trial information: NCT04698915 .
The EPOCH trial: Identifying key patient subgroups to optimize treatment planning.
Authors: William P. Harris, Riad Salem
Journal: Journal of Clinical Oncology (2023)

130 Background: The primary objective of the original EPOCH trial was to evaluate the potential benefit of adding transarterial radioembolization (TARE) with yttrium-90 glass microspheres to second-line chemotherapy (chemo) versus chemo alone in patients with liver-dominant metastatic colorectal cancer (mCRC). Randomization was stratified by key prognostic factors, including KRAS status; however, it did not account for ECOG status and baseline CEA levels. We present post-hoc analyses investigating the impact of prognostic factors on primary and secondary endpoints to help optimize patient selection. Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter Phase 3 trial. Primary endpoints were progression-free survival (PFS) and hepatic PFS (hPFS). Overall survival (OS) and time to deterioration of quality of life (TTDQOL) were secondary. Post-hoc analyses of the following subgroups were performed: Subgroup A (excluding patients with both ECOG=1 and CEA≥35ng/mL) and Subgroup B (patients with KRAS wild-type and either ECOG=0 or CEA&lt;35ng/mL). Kaplan-Meier analyses, hazard ratios (HRs) and log-rank tests were used to compare outcomes between TARE plus chemo and chemo only groups. Results: In Subgroup A, 160 (75.1%) patients were randomized to chemo only, versus 143 (66.5%) to the TARE arm. In Subgroup B, 91 (42.7%) patients were randomized to chemo only, versus 77 (35.8%) to the TARE arm. Results are shown for PFS, hPFS, OS, and TTDQOL in the intent-to-treat population. In both subgroups A and B, PFS, hPFS, and TTDQOL were significantly improved for the TARE plus chemo arm as compared to the chemo only arm; no OS difference was found. Conclusions: Careful patient selection using multiple prognostic factors is necessary to identify those who will benefit most from TARE with second-line chemo. Prognostic factors were important in identifying the level of benefit seen in patients treated with TARE and chemo versus chemo alone. Clinical trial information: NCT01483027 . [Table: see text]
Plasma central carbon metabolite changes associated with KRAS mutation and circulating tumor DNA (ctDNA) status in colorectal cancer (CRC).
Authors: Daniel Myung Kim, Francesca Paola Aguirre, Alexandra Gangi, Rocio Alvarez, Lisa Zhou, Johanna ten Hoeve, Yi Jou Liao, Thomas Graeber, Andrew Eugene Hendifar, Arsen Osipov, Kamya Sankar, May Thet Cho, Anser Abbas, John Davelaar, Megan Philippa Hitchins, Jun Gong
Journal: Journal of Clinical Oncology (2023)

181 Background: KRAS mutations have been widely characterized as markers of poor prognosis in CRC. In stage IV CRC, KRAS mutations are predictive of benefit to anti-EGFR therapy. ctDNA has increasingly been recognized as a prognostic biomarker in CRC as well. We evaluated the association between plasma metabolites and KRAS mutation or ctDNA status in a longitudinal, observational cohort of patients with stage I-IV CRC. Methods: This was a retrospective analysis of prospectively collected blood samples from a single-institute cohort of patients with stage I-IV CRC. All blood samples were collected at pre-chemotherapy baseline. A modified Epi proColon 2.0 CE (Epigenomics AG) assay was used for plasma ctDNA testing on the methylated SEPTIN9 gene (mSEPT9). ctDNA positivity was defined as a mSEPT9 percentage of methylation reference (PMR) value greater than zero. Up to 150 metabolites of central carbon metabolism were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by ANOVA. The mean AUC was used in patients with metabolites measured from &gt; 1 timepoint of collection. Patients were stratified by ctDNA status (positive or negative) and KRAS mutant (MT) or wildtype (WT) status. Results: A total of 32 patients were included with median age 65 years (range 20-90). The majority were female (53%) and had stage IV disease (78%). Of 25 patients with stage IV CRC, 88% had pre-chemotherapy blood samples collected in the first-line setting. Most patients were KRAS MT (44%) compared to KRAS WT (37%) or unknown KRAS status (19%). The most common KRAS MT subtypes were G12D (29%), G12V (29%), G13D (21%), and G12C (14%). The mean overall survival in this cohort was 27.4 months while the mean mSEPT9 PMR value was 2553.6. When stratified by ctDNA status, ctDNA positivity was associated with decreased levels of essential amino acids (lysine, methionine, threonine) and the non-essential amino acid arginine (all p &lt; 0.05). Compared to KRAS WT tumors, KRAS MT tumors were associated with increased levels of proline, phenylalanine, and intermediates of glycolysis (lactate), MTA cycle (SAM, 5-Methioadenosine), and O-GlcNAcylation (GlcNac, all p &lt; 0.05). Conclusions: We are the first to demonstrate the feasibility of associating central carbon metabolites with ctDNA and KRAS mutation status. As ctDNA positivity and KRAS MT status have evolving prognostic potential in CRC, associated metabolic signatures may identify metabolic pathways for novel biomarker development. Our findings also show that KRAS MT CRC appears to be enriched in intermediates of glycolytic, methyl donor, and O-GlcNAcylation pathways.
Phase 2 randomized, active-controlled, multicenter trial to assess the safety and efficacy of RRx-001 + irinotecan vs. regorafenib + irinotecan in third/fourth-line colorectal cancer.
Authors: Tony R. Reid, Nacer Abrouk, Bryan Oronsky, Scott Caroen, George A. Fisher
Journal: Journal of Clinical Oncology (2023)

97 Background: RRx-001 is a novel cysteine-targeted alkylating agent that, upon binding, under severe hypoxia, which is primarily present in tumors, releases nitric oxide (NO) and other cytotoxic metabolites. The primary biological activities of this hybrid molecule include macrophage repolarization, CD47 downregulation, and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib + irinotecan in 3 rd /4 th line colorectal cancer that previously received treatment with irinotecan. Methods: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to regorafenib + irinotecan (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month induction therapy or “primer” followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the ITT efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months followed by intravenous infusion of irinotecan at 180 mg/m 2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m 2 on day 1 in a 21-day cycle. Results: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, two-sided log-rank test, p = 0.0030). Overall response rate was 20.8% for RxI vs. 0% for RegI. Moreover, the toxicity profile of RxI was substantially improved compared with RegI. Conclusions: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed “signal” accompanied by a sufficient safety profile. Clinical trial information: NCT02096354 .
Impact of etiology of hepatocellular carcinoma on treatment outcomes in a real-world database.
Authors: Timothy J Brown, Ronac Mamtani, Phyllis A. Gimotty, Thomas Benjamin Karasic, Yu-Xiao Yang
Journal: Journal of Clinical Oncology (2023)

508 Background: Hepatocellular carcinoma (HCC) is a common and deadly form of liver cancer. Systemic therapy with combination atezolizumab and bevacizumab (A/B) is the new treatment standard; yet fewer than 30% experience treatment response. The etiology of HCC (viral, alcohol, or NASH) and its impact on treatment response is unknown. Thus, we sought to determine the impact of etiology on survival outcomes of patients treated with A/B. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Patients with HCC receiving first-line A/B after January 1, 2020 were eligible for inclusion. We used a validated algorithm to adjudicate cohort by likely etiology (viral, alcohol and NASH). The primary outcome was median real-world overall survival (OS), defined from initial receipt of A/B until death or censored at last receipt of A/B by etiology. The secondary outcome was real-world time to treatment discontinuation (TTD -a validated surrogate that approximates progression-free survival) defined as time from initial receipt of A/B to progression, death, or treatment discontinuation for more than 120 days or censored at last clinical contact by etiology. The Kaplan-Meier method, Cox proportional hazards model and the log-rank test was used to test for differences between etiologies. Results: In total, 429 eligible HCC patients were included (n=216, 50.3% Viral; n=68, 15.8% Alcohol; n=145, 33.8%, NASH). In the total cohort, median OS was 9.4 months (95% CI 7.1-10.9) and median TTD was 5.7 months (5.0-7.0); by etiology, OS medians were 10.1 (7.2-14.0), 9.8 (6.1-13.9), 7.5 (5.3-11.0) months, and TTD medians were 6.1 (5.0-8.0), 5.8 (3.7-7.8), and 5.5 (2.6-7.0) months, for Viral-HCC, Alcohol-HCC, and NASH-HCC respectively. No significant difference in the hazard of death or TTD by etiology were observed in the unadjusted or adjusted Cox regression analyses (see table). The multivariate model included age, ECOG performance status, receipt of prior locoregional therapy, albumin-bilirubin (ALBI) grade, and baseline aspartate aminotransferase. Conclusions: In this large cohort study of US patients with HCC, we did not identify a significant association between etiology and survival or time to treatment discontinuation outcomes, although outcomes were numerically worse in patients with NASH. Although the underlying microenvironment and oncogenesis may differ by etiology, further research is needed to identify those most likely to benefit from A/B. [Table: see text]
A pilot study for single cell RNA-sequencing of patient-derived pancreatobiliary cancer organoid.
Authors: Bomi Kim, Minseok Seo, Sinwoo Park, Jiho Park, Jeonghwa Jin, Jinkyeong Park, Jong-Chan Lee, Jin-Hyeok Hwang, Jaihwan Kim
Journal: Journal of Clinical Oncology (2023)

739 Background: For precision medicine, patient-derived organoid (PDO) is regarded as one of the promising models. However, current PDOs were mainly derived from surgical specimens. We aimed to analyze the single cell RNA-sequencing (scRNA-seq) of PDO from various sampling methods with different pathologic outcomes. Methods: In 2021, three pancreatic cancer and one gallbladder cancer samples were collected from surgical specimen, endoscopic ultrasound guided-fine needle biopsy (EUS-FNB), and endoscopic retrograde cholangiopancreatography (ERCP)-guided biopsy. The samples were mechanically dissociated with dissociation buffer and incubated using shaking incubator. Dissociated cells were seeded into growth factor reduced Matrigel. From these PDOs, we generated scRNA-seq data in each experimental design, and corrected batch effects that could occur when multiple samples are considered simultaneously in downstream analysis. Marker genes representing each cell subcluster were identified, and statistical hypothesis tests were performed to identify genes differentially expressed according to differences in biopsy methods and/or pathological results. Results: We found the optimal 8 types of sub cell-type clusters with a resolution parameter of 0.3 in clustering analysis based on the Uniform Manifold Approximation and Projection (UMAP) algorithm in terms of silhouette score. As a result of examining the expression levels of KRT19, a marker gene for malignant ductal cells, and RGS5, a stellate marker gene, which showed the same pattern as the existing PDAC transcriptome studies, it was confirmed that most of the cells derived from PDOs were malignant ductal cells. Finally, we identified a heterogeneous effect on gene expression patterns in ductal cells depending on not only pathological positivity, but also biopsy methods for organoid. Conclusions: According to our scRNA-seq, most cells were malignant cells and EUS-FNB could be a good sampling method for PDOs. However, further analysis about a heterogeneous effect on gene expression patterns is necessary.[Table: see text]
Real-world impact of initial treatment modality on survival outcomes in patients with stage I-III pancreatic ductal adenocarcinoma.
Authors: Ajay Prakash, Joschua Schwanke, Thuy-Hong Le-Kumar, Brooke Patterson, Schelomo Marmor, Christopher Tignanelli, Eric Hans Jensen, Emil Lou
Journal: Journal of Clinical Oncology (2023)

684 Background: Management of non-metastatic pancreas cancer has been extensively studied in clinical trials over the past two decades, with a growing body of non-randomized data supporting the use of neoadjuvant chemotherapy in combination with surgery. Guidelines now recommend use of this treatment paradigm, but real-world follow-up is critical in understanding how these recommendations are translated into the clinic. Using real-world data, we aimed to evaluate the treatment modalities and subsequent survival outcomes for patients diagnosed with pancreatic adenocarcinoma within the MHealth/Fairview medical system. Methods: We identified 844 patients diagnosed with stage I-III pancreatic adenocarcinoma within the MHealth/Fairview system (Minneapolis, MN) from 2001-2021 with EHR data enriched by cancer registry abstracted data. Diagnoses were confirmed with ICD-10 coding and clinical staging. Patients were stratified by initial treatment with either surgery (N = 345) or neoadjuvant-intent chemotherapy (n = 499). Correlation between initial treatment modality, demographic identifiers, and time to treatment was calculated using both Pearson and Spearman method. Effect of initial treatment modality on overall survival was calculated using a Cox proportional Hazard (CPH) model controlling for age, sex, clinical stage, and time to treatment initiation (TTI). A sub-analysis with race was performed on samples where these data were available. Results: Relative to neoadjuvant chemotherapy, up-front surgery was associated with a significantly improved overall survival (Hazard Ratio (HR) 0.55 95% Confidence Interval (CI): 0.37 – 0.76; p &lt; 0.001), when controlling for age, sex, clinical stage, and TTI. Surgical patients also had shorter mean TTI values (21 days; p &lt; 0.001) relative to chemotherapy (28 days), and a slightly younger patient population (mean age 63, vs 66 for chemotherapy, p = &lt; 0.001; rho = -0.14). We observed no significant correlation between age (p = 0.027) or TTI (p = 0.12) and survival within this population. We noted no significant correlation between race, sex, or clinical stage and initial treatment modality or overall survival. Conclusions: We observed that MHealth/Fairview system patients who received upfront surgery for stage I-III pancreas cancers demonstrated improved overall survival relative to other treatment modalities, even after controlling for the differences in age and TTI found between these patients and those who undergo initial chemotherapy. This is likely due to a multitude of factors not readily captured within this data set, including surgical patient selection and tumor biology. Further work is needed to understand why these findings diverge from study norms, and to optimize care for all patients with pancreatic adenocarcinoma.
Comparison of pancreatic cancer outcomes diagnosed in surveillance and the general population: A propensity score-matched analysis.
Authors: Derk C.F. Klatte, Bas Boekestijn, Anke M. Onnekink, Friedo W. Dekker, Lydia G. van der Geest, Martin N.J.M.M. Wasser, Shirin Feshtali, J. Sven D. Mieog, Hans Morreau, Thomas P. Potjer, Akin Inderson, Jurjen J. Boonstra, Hans F.A. Vasen, Saskia Luelmo, Jeanin E. van Hooft, Bert A. Bonsing, Monique E. van Leerdam
Journal: Journal of Clinical Oncology (2023)

690 Background: Recent pancreatic cancer surveillance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) in patients with a CDKN2A/p16 pathogenic variant (PV) diagnosed during surveillance are better as compared to PDAC patients diagnosed outside surveillance. Methods: In a propensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage and survival between patients diagnosed in surveillance with non-surveillance PDAC patients. Survival analysis were repeated after adjustment for lead-time bias. Results: Between January 2000 and December 2020, 43 762 patients with PDAC were identified from the NCR. Thirty-one patients with PDAC in surveillance were matched in a 1:5 ratio with 155 non-surveillance patients based on age at diagnosis, sex, and year of diagnosis. In total, 71% of patients in surveillance, as compared to 16% of non-surveillance patients underwent a surgical resection (OR 14.03; 95% CI, 5.92 – 35.85). In surveillance, 39% of patients was diagnosed with stage I cancer, as compared to 6% of non-surveillance PDAC patients (OR 0.10; 95% CI, 0.04 – 0.21). Patients in surveillance had a better prognosis, reflected by a 3-year survival of 32.4% and a median overall survival (OS) of 26.8 months vs. 1.4% 3-year survival and 5.3 months median OS in non-surveillance patients (HR 0.22; 95% 0.14 – 0.36). After adjustment for lead time, PDAC diagnosis in surveillance remained strongly associated with improved survival. Conclusions: Surveillance for PDAC in carriers of a CDKN2A/p16 PV results in earlier detection, increased resectability and improved survival as compared to non-surveillance PDAC patients.[Table: see text]